This invention relates to rifamycin derivatives having antimicrobial activity, compositions containing the compounds, and methods for treatment and prevention of microbial infections. The compounds of the current invention exhibit potent antimicrobial activity and improved activity against rifamycin-resistant bacteria. In particular, the compounds of the current invention relate to a series of novel spiro rifamycin derivatives which demonstrated potent antibiotic activity.
Rifamycins are potent antibiotics targeting bacterial RNA polymerase. The therapeutic applications of the naturally-occurring rifamycins are limited due to their poor oral bioavailability, weak activity against Gram-negative pathogens and low distribution into the infected tissues. Significant efforts have been made toward identifying semi-synthetic rifamycin derivatives to address these deficiencies. As a result, many semi-synthetic rifamycin derivatives with improved spectra and pharmacological profiles have been identified. Among the semi-synthetic compounds, rifampin, rifabutin and rifapetine have been developed into therapeutic agents and are currently used for the treatment of tuberculosis and other microbial infections (Farr, Rifamycins).
At present, one of the major problems associated with the rifamycin class of antimicrobial agents is the rapid development of microbial resistance. Mutations in RNA polymerase are mainly responsible for the high frequency of microbial resistance to rifamycins. Consequently, rifamycins are currently used only in combination therapies to minimize the development of resistance to this class of drug.
Reference is made to U.S. Pat. No. 4,219,478 that disclosed a series of spiro compounds which contain a 5-membered imidazoline ring, fused to the 3,4-position of rifamycin. The compounds of the current invention are structurally distinct, containing a 6-membered heterocycle fused to the 3,4-position of rifamycin. The compounds of the current invention have demonstrated improved activity against rifamycin resistant strains.
References are also made to U.S. Pat. No. 4,690,919, U.S. Pat. No. 4,859,661, U.S. Pat. No. 4,965,261, and U.S. Pat. No. 4,983,602 that disclosed a series of 6-membered heterocyclic rifamycin derivatives. Compounds of the current invention are structurally distinct by having a spiro system in the structure.